Aza-benzothiophenyl compounds and methods of use

ABSTRACT

The invention relates to azabenzothiophenyl compounds of Formula I with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzothiophenyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

RELATED APPLICATIONS

This application is a non-provisional application filed under 37 CFR1.53(b)(1), claiming priority under 35 USC 119(e) to provisionalapplication No. 60\839,163 filed Aug. 21, 2006, and provisionalapplication No. 60/871,600 filed Dec. 22, 2006, and provisionalapplication No. 60/917,624 filed May 11, 2007, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to azabenzothiophenyl compounds with anti-cancerand/or anti-inflammatory activity and more specifically toazabenzothiophenyl compounds which inhibit MEK kinase activity. Theinvention also relates to methods of using the compounds for in vitro,in situ, and in vivo diagnosis or treatment of mammalian cells, orassociated pathological conditions.

BACKGROUND OF THE INVENTION

In the quest to understand how Ras transmits extracellular growthsignals, the MAP (mitogen-activated protein) kinase (MAPK) pathway hasemerged as the crucial route between membrane-bound Ras and the nucleus.The MAPK pathway encompasses a cascade of phosphorylation eventsinvolving three key kinases, namely Raf, MEK (MAP kinase kinase) and ERK(MAP kinase). Active GTP-bound Ras results in the activation andindirect phosphorylation of Raf kinase. Raf then phosphorylates MEK1 and2 on two serine residues (S218 and S222 for MEK1 and S222 and S226 forMEK2) (Ahn et al., Methods in Enzymology 2001, 332, 417-431). ActivatedMEK then phosphorylates its only known substrates, the MAP kinases, ERK1and 2. ERK phosphorylation by MEK occurs on Y204 and T202 for ERK1 andY185 and T183 for ERK2 (Ahn et al., Methods in Enzymology 2001, 332,417-431). Phosphorylated ERK dimerizes and then translocates to thenucleus where it accumulates (Khokhlatchev et al., Cell 1998, 93,605-615). In the nucleus, ERK is involved in several important cellularfunctions, including but not limited to nuclear transport, signaltransduction, DNA repair, nucleosome assembly and translocation, andmRNA processing and translation (Ahn et al., Molecular Cell 2000, 6,1343-1354). Overall, treatment of cells with growth factors leads to theactivation of ERK1 and 2 which results in proliferation and, in somecases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74,49-139).

There has been strong evidence that genetic mutations and/oroverexpression of protein kinases involved in the MAP kinase pathwaylead to uncontrolled cell proliferation and, eventually, tumorformation, in proliferative diseases. For example, some cancers containmutations which result in the continuous activation of this pathway dueto continuous production of growth factors. Other mutations can lead todefects in the deactivation of the activated GTP-bound Ras complex,again resulting in activation of the MAP kinase pathway. Mutated,oncogenic forms of Ras are found in 50% of colon and >90% pancreaticcancers as well as many others types of cancers (Kohl et al., Science1993, 260, 1834-1837). Recently, bRaf mutations have been identified inmore than 60% of malignant melanoma (Davies, H. et al., Nature 2002,417, 949-954). These mutations in bRaf result in a constitutively activeMAP kinase cascade. Studies of primary tumor samples and cell lines havealso shown constitutive or overactivation of the MAP kinase pathway incancers of pancreas, colon, lung, ovary and kidney (Hoshino, R. et al.,Oncogene 1999, 18, 813-822).

MEK has emerged as an attractive therapeutic target in the MAP kinase,cascade pathway. MEK, downstream of Ras and Raf, is highly specific forthe phosphorylation of MAP kinase; in fact, the only known substratesfor MEK phosphorylation are the MAP kinases, ERK1 and 2. Inhibition ofMEK has been shown to have potential therapeutic benefit in severalstudies. For example, small molecule MEK inhibitors have been shown toinhibit human tumor growth in nude mouse xenografts, (Sebolt-Leopold etal., Nature-Medicine 1999, 5 (7), 810-816); Trachet et al., AACR Apr.6-10, 2002, Poster #5426; Tecle, H. IBC 2.sup.nd InternationalConference of Protein Kinases, Sep. 9-10, 2002), block static allodyniain animals (WO 01/05390 published Jan. 25, 2001) and inhibit growth ofacute myeloid leukemia cells (Milella et al., J Clin Invest 2001, 108(6), 851-859).

Several small molecule MEK inhibitors have also been discussed in, forexample, WO02/06213, WO 03/077855 and WO03/077914. There still exists aneed for new MEK inhibitors as effective and safe therapeutics fortreating a variety of proliferative disease states, such as conditionsrelated to the hyperactivity of MEK, as well as diseases modulated bythe MEK cascade.

SUMMARY OF THE INVENTION

The invention relates generally to azabenzothiophenyl compounds ofFormula I (and/or solvates and salts thereof) with anti-cancer and/oranti-inflammatory activity, and more specifically with MEK kinaseinhibitory activity. Certain hyperproliferative and inflammatorydisorders are characterized by the modulation of MEK kinase function,for example by mutations or overexpression of the proteins. Accordingly,the compounds of the invention and compositions thereof are useful inthe treatment of hyperproliferative disorders such as cancer and/orinflammatory diseases such as rheumatoid arthritis.

wherein:

Z¹ is CR¹ or N;

Z² is CR² or N;

Z³ is CR³ or N;

Z⁴ is CR⁴ or N;

where one or two of Z¹, Z², Z³, and Z⁴ are N;

R¹, R², R³ and R⁴ are independently selected from H, halo, CN, CF₃,—OCF₃, —NO₂, —(CR¹⁴R¹⁵)_(n)C(═Y)R¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y)OR¹¹,—(CR¹⁴R¹⁵)_(n)C(═Y)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)SR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹¹C(═Y)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹⁴C(═Y)OR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹³C(═Y)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹—(CR¹⁴R¹⁵)_(n)OC(═Y)R¹¹,—(CR¹⁴R¹⁵)_(n)OC(═Y)OR¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)OS(O)₂(OR¹¹), —(CR¹⁴R¹⁵)_(n)OP(═Y)(OR¹¹)(OR¹²),—(CR¹⁴R¹⁵)_(n)OP(OR¹¹)(OR¹²), —(CR¹⁴R¹⁵)_(n)S(O)R¹¹,—(CR¹⁴R¹⁵)_(n)S(O)₂R¹¹, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)S(O)(OR¹¹), —(CR¹⁴R¹⁵)_(n)S(O)₂(OR¹¹),—(CR¹⁴R¹⁵)_(n)SC(═Y)R¹¹, —(CR¹⁴R¹⁵)_(n)SC(═Y)OR¹¹,—(CR¹⁴R¹⁵)_(n)SC(═Y)NR₁₁R¹², C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl;

R⁵ and R⁶ are independently selected from H or C₁-C₁₂ alkyl;

X¹ is selected from R¹¹, —OR¹¹, —NR¹¹R¹², —S(O)R¹¹, and —S(O)₂R¹¹; whenX¹ is R¹¹ or —OR¹¹, R¹¹ or —OR¹¹ of X¹ and —R⁵ are optionally takentogether with the nitrogen atom to which they are attached to form a 4-7membered saturated or unsaturated ring having 0-2 additional heteroatomsselected from O, S and N, wherein said ring is optionally substitutedwith one or more groups selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo,—Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹;

X² is selected from carbocyclyl, heterocyclyl, aryl, and heteroaryl;

R¹¹, R¹² and R¹³ are independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl,

or R¹¹ and R¹² together with the nitrogen to which they are attachedform a 3-8 membered saturated, unsaturated or aromatic ring having 0-2heteroatoms selected from O, S and N, wherein said ring is optionallysubstituted with one or more groups selected from halo, CN, CF₃, —OCF₃,—NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl);

R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, aryl,carbocyclyl, heterocyclyl, and heteroaryl;

m and n are independently selected from 0, 1, 2, 3, 4, 5, or 6;

Y is independently O, NR¹¹, or S;

wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl and heteroaryl of R¹, R², R³, R⁴, R⁵, R⁶, X¹, X², R¹¹, R¹², R¹³,R¹⁴, and R¹⁵ is independently optionally substituted with one or moregroups independently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo,—Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n) C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷)—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR)—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, (CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹;

each R¹⁶, R¹⁷ and R¹⁸ is independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, whereinsaid alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more groups selectedfrom halo, CN, —OCF₃, CF₃, —NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),—C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆alkyl), —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl),—NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), and —N(C₁-C₆alkyl)C(O)O(C₁-C₆ alkyl);

or R¹⁶ and R¹⁷ together with the nitrogen to which they are attachedform a 3-8 membered saturated, unsaturated or aromatic ring having 0-2heteroatoms selected from O, S and N, wherein said ring is optionallysubstituted with one or more groups selected from halo, CN, —OCF₃, CF₃,—NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl);

R¹⁹ and R²⁰ are independently selected from H, C₁-C₁₂ alkyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-carbocyclyl, —(CH₂)_(n)-heterocyclyl, and—(CH₂)_(n)-heteroaryl;

R²¹ is C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein each member of R²¹ isoptionally substituted with one or more groups selected from halo, oxo,CN, —OCF₃, CF₃, —NO₂, C₁-C₆ alkyl, —OH, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl),—CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),—NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl),—NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), and —N(C₁-C₆alkyl)C(O)O(C₁-C₆ alkyl);

each Y′ is independently O, NR²², or S; and

R²² is H or C₁-C₁₂ alkyl.

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of Formula I (and/or solvates andsalts thereof) and a carrier (a pharmaceutically acceptable carrier).The present invention also includes a composition (e.g., apharmaceutical composition) comprising a compound of Formula I (and/orsolvates and salts thereof) and a carrier (a pharmaceutically acceptablecarrier), further comprising a second chemotherapeutic and/or a secondanti-inflammatory agent. The present compositions are useful forinhibiting abnormal cell growth or treating a hyperproliferativedisorder in a mammal (e.g., human). The present compositions are alsouseful for treating inflammatory diseases in a mammal (e.g., human).

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I (and/or solvates and saltsthereof) or a composition thereof, alone or in combination with a secondchemotherapeutic agent.

The present invention includes a method of treating an inflammatorydisease in a mammal (e.g., human) comprising administering to saidmammal a therapeutically effective amount of a compound of Formula I(and/or solvates and salts thereof) or a composition thereof, alone orin combination with a second anti-inflammatory agent.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or, associated pathological conditions.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms. Examples of alkyl groups include, but are not limited to, methyl(Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (1-Bu, i -butyl, —CH₂CH(CH₃)₂),2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu,t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)₂), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl,1-octyl, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical includes radicals having “cis” and “trans” orientations,or alternatively, “E” and “Z” orientations. Examples include, but arenot limited to, ethylenyl or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), andthe like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms with at least one site ofunsaturation, i.e., a carbon -carbon, sp triple bond. Examples include,but are not limited to, ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH),and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms as a monocyclic ring or 7to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6]or [6,6] system, and bicyclic -carbocycles having 9 or 10 ring atoms canbe arranged as a bicyclo [5,6] or [6,6] system, or as bridged systemssuch as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-18 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Some aryl groups are representedin the exemplary structures as “Ar”. Aryl includes bicyclic radicalscomprising an aromatic ring fused to a saturated, partially unsaturatedring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, indenyl, indanyl,1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthyl, and the like.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to 18 ring atoms in which at leastone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur,the remaining ring atoms being C, where one or more ring atoms isoptionally substituted independently with one or more substituentsdescribed below. A heterocycle may be a monocycle having 3 to 7 ringmembers (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O,P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atomsand 1 to 6 heteroatoms selected from N, O, P, and S), for example: abicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are describedin Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and9; “The Chemistry of Heterocyclic Compounds, A series of Monographs”(John Wiley & Sons, New York, 1950 to present), in particular Volumes13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated ring, or aromaticcarbocyclic or heterocyclic ring. Examples of heterocyclic ringsinclude, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Spiromoieties are also included within the scope of this definition. Examplesof a heterocyclic group wherein ring atoms are substituted with oxo (═O)moieties are pyrimidinonyl and 1,1dioxo -thiomorpholinyl.

The term “heteroaryl” refers to a monovalent aromatic radical of 5- or6-membered rings, and includes fused ring systems (at least one of whichis aromatic) of 5-18 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

The heterocycle or heteroaryl groups may be carbon (carbon-linked) ornitrogen (nitrogen-linked) attached where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The term “halo” refers to F, Cl, Br or I. The heteroatoms present inheteroaryl or heterocyclcyl include the oxidized forms such as N⁺→O⁻,S(O) and S(O)₂.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application. “Abnormal cell growth”, asused herein, unless otherwise indicated, refers to cell growth that isindependent of normal regulatory mechanisms (e.g., loss of contactinhibition). This includes, for example, the abnormal growth of: (1)tumor cells (tumors) that proliferate by expressing a mutated tyrosinekinase or overexpression of a receptor tyrosine kinase; (2) benign andmalignant cells of other proliferative diseases in which aberranttyrosine kinase activation occurs; (3) any tumors that proliferate byreceptor tyrosine kinases; (4) any tumors that proliferate by aberrantserine/threonine kinase activation; and (5) benign and malignant cellsof other proliferative diseases in which aberrant serine/threoninekinase activation occurs.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, acute leukemia, as well as head/brain andneck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includeErlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®,Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate(GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin(Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin(Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERBI®, GSK572016, GlaxoSmith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, BayerLabs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271;Sugen), alkylating agents such as thiotepa and CYTOXAN®cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gamma1I and calicheamicinomegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino -doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ilinois), andTAXOTERE® (doxetaxel; Rhône-Poulenc Rorer, Antony, France);chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5) -imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptablesalts, acids and derivatives of any of the above. Other anti-angiogenicagents include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9(matrix-metalloproteinase 9) inhibitors, COX-II (cyclooxygenase II)inhibitors, and VEGF receptor tyrosine kinase inhibitors. Examples ofsuch useful matrix metalloproteinase inhibitors that can be used incombination with the present compounds/compositions are described in WO96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516,WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606,046, EP931,788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO99/07675, EP 945864, U.S. Pat. No. 5,863,949, U.S. Pat. No. 5,861,510,and EP 780,386, all of which are incorporated herein in their entiretiesby reference. Examples of VEGF receptor tyrosine kinase inhibitorsinclude4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds such asthose disclosed in PCT Publication Nos. WO 97/22596, WO 97/30035, WO97/32856, and WO 98/13354).

Other examples of chemotherapeutic agents that can be used incombination with the present compounds include inhibitors of PI3K(phosphoinositide-3 kinase), such as those reported in Yaguchi et al(2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; U.S. Pat. Nos.7,173,029; 7,037,915; 6,608,056; 6,608,053; 6,838,457; 6,770,641;6,653,320; 6,403,588; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO2007/042806; WO 2007/042810; WO 2004/017950; U.S. 2004/092561; WO2004/007491; WO 2004/006916; WO 2003/037886; U.S. 2003/149074; WO2003/035618; WO 2003/034997; U.S. 2003/158212; EP 1417976; U.S.2004/053946; JP 2001247477; JP 08175990; JP 08176070; U.S. Pat. No.6,703,414; and WO 97/15658, all of which are incorporated herein intheir entireties by reference. Specific examples of such PI3K inhibitorsinclude SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.).

The term “inflammatory diseases” as used in this application includes,but not limited to, rheumatoid arthritis, atherosclerosis, congestivehear failure, inflammatory bowel disease (including, but not limited to,Crohn's disease and ulcerative colitis), chronic obstructive pulmonarydisease in the lung, fibrotic disease in the liver and kidney, Crohn'sdisease, skin diseases such as psoriasis, eczema and scleroderma,osteoarthritis, multiple sclerosis, asthma, diseases and disordersrelated to diabetic complications, fibrotic organ failure in organs suchas lung, liver, kidney, and inflammatory complications of thecardiovascular system such as acute coronary syndrome.

An “anti-inflammatory agent” is a compound useful in the treatment ofinflammation. Examples of anti-inflammatory agents include injectableprotein therapeutics such as Enbrel®, Remicade®, Humira® and Kineret®.Other examples of anti-inflammatory agents include non-steroidalanti-inflammatory agents (NSAIDs), such as ibuprofen or aspirin (whichreduce swelling and alleviate pain); disease-modifying anti-rheumaticdrugs (DMARDs) such as methotrexate; 5-aminosalicylates (sulfasalazineand the sulfa-free agents); corticosteroids; immunomodulators such as6-mercaptoputine (“6-MP”), azathioprine (“AZA”), cyclosporines, andbiological response modifiers such as Remicade® (infliximab) and Enbrel®(etanercept); fibroblast growth factors; platelet derived growthfactors; enzyme blockers such as Arava® (leflunomide); and/or acartilage protecting agent such as hyaluronic acid, glucosamine, andchondroitin.

The term “prodrug” as used in this application refers to a precursor orderivative form of a compound of the invention that is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). The prodrugs of this invention include,but are not limited to, ester-containing prodrugs, phosphate-containingprodrugs, thiophosphate-containing prodrugs, sulfate-containingprodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs,glycosylated prodrugs, β-lactam-containing prodrugs, optionallysubstituted phenoxyacetamide-containing prodrugs, optionally substitutedphenylacetamide-containing prodrugs, 5-fluorocytosine and other5-fluorouridine prodrugs which can be converted into the more activecytotoxic free drug. Examples of cytotoxic drugs that can be derivatizedinto a prodrug form for use in this invention include, but are notlimited to, compounds of the invention and chemotherapeutic agents suchas described above.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, hydroxylation,reduction, hydrolysis, amidation, deamidation, esterification,deesterification, enzymatic cleavage, and the like, of the administeredcompound. Accordingly, the invention includes metabolites of compoundsof the invention, including compounds produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as MEK inhibitors disclosed herein and, optionally, achemotherapeutic agent) to a mammal. The components of the liposome arecommonly arranged in a bilayer formation, similar to the lipidarrangement of biological membranes.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomer” refers to compounds which have identicalchemical constitution and connectivity, but different orientations oftheir atoms in space that cannot be interconverted by rotation aboutsingle bonds.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as crystallization, electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g.,sodium and potassium) salts, alkaline earth metal (e.g., magnesium)salts, and ammonium salts. A pharmaceutically acceptable salt mayinvolve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

The term “protecting group” refers to a substituent that is commonlyemployed to block or protect a particular functionality while reactingother functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include phenylsulfonylethyl,cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula I,”, unless otherwise indicated,include compounds of Formula I and stereoisomers, geometric isomers,tautomers, solvates, metabolites, salts (e.g., pharmaceuticallyacceptable salts) and prodrugs thereof.

The present invention provides azabenzothiophenyl compounds of Formula Ias described above useful as kinase inhibitors, particularly useful asMEK kinase inhibitors. The present invention includes compounds ofFormulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, II-a, II-b, II-c,II-d, II-e, II-f, Ii-g, II-h, II-i, III-a, III-b, III -c, III-d, III-e,III-f, III-g, III-h, and III-i, and all other variables are as definedin Formula I.

In an embodiment of the present invention, compounds are of FormulaeI-b, I-f, I-g, I-h, II-b, II-f, II-g, II-h, III-b, III-f, III-g andIII-h, and all other variables are as defined in Formula I.

In an embodiment of the present invention, compounds are of FormulaIII-c, and all other variables are as defined in Formula I.

In an embodiment of the present invention, R¹ is H, halo, CN, CF₃,—NR¹¹R¹², —OR¹¹, —SR¹¹, —C(═O)NR¹¹R¹²; or C₁-C₆ alkyl, and all othervariables are as defined in Formula I, I-a, I-b, I-d, I-f, I-g, II-a,II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f, or III-g.

In another embodiment of the present invention, R¹ is H, halo, CN, CF₃,C₁-C₆ alkyl, —NR¹¹R¹² wherein R¹¹ and R¹² are independently H or C₁-C₆alkyl, —OR¹¹ wherein R¹¹ is H or C₁-C₆ alkyl, or —SR¹¹ wherein R¹¹ is Hor C₁-C₆ alkyl; and all other variables are as defined in Formula I,I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d, II-f, II-g, III-a, III-b,III-d, III-f, or III-g.

In another embodiment of the present invention, R¹ is H, Cl, CN, CF₃,methyl, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, or —OCH₃; and all other variablesare as defined in Formula I, I-a, I-b, I-d, I-f, I-g, II-a, II-b, II-d,II-f, II-g, III-a, III-b, III-d, III-f, or III-g.

In another embodiment of the present invention, R¹ is H; and all othervariables are as defined in Formula I, I-a, I-b, I-d, I-f, I-g, II-a,II-b, II-d, II-f, II-g, III-a, III-b, III-d, III-f, or III-g.

In an embodiment of the present invention, R² is H, halo, CN, CF₃,—NR₁₁R¹², —OR¹¹, —SR¹¹, —C(═O)NR¹¹R¹², or C₁-C₆ alkyl, and all othervariables are as defined in Formula I, I-a, I-c, I-d, I-e, I-i, II-a,II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e, or III-i, or asdefined above.

In another embodiment of the present invention, R² is H, halo, CN, CF₃,C₁-C₆ alkyl, —NR¹¹R¹² wherein R¹¹ and R¹² are independently H or C₁-C₆alkyl, —OR¹¹ wherein R¹¹ is H or C₁-C₆ alkyl, or —SR¹¹ wherein R¹¹ is Hor C₁-C₆ alkyl; and all other variables are as defined in Formula I,I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c,III-d, III-e, or III-i, or as defined above.

In another embodiment of the present invention, R² is H, Cl, CN, CF₃,methyl, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, or —OCH₃; and all other variablesare as defined in Formula I, I-a, I-c, I-d, I-e, I-i, II-a, II-c, II-d,II-e, II-i, III-a, III-c, III-d, III-e, or III-i, or as defined above.

In an embodiment of the present invention, R³ is H, halo, CN, CF₃,—NR¹¹R¹², —OR¹¹, —SR¹¹, —C(═O)NR¹¹R¹², or C₁-C₆ alkyl, and all othervariables are as defined in Formula I, I-a, I-c, I-d, I-e, I-i, II-a,II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e, or III-i, or asdefined above.

In another embodiment of the present invention, R³ is H, halo, CF₃,C₁-C₆ alkyl; and all other variables are as defined in Formula I, I-a,I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d,III-e, or III-i, or as defined above.

In another embodiment of the present invention, R³ is H, F, CF₃, ormethyl; and all other variables are as defined in Formula I, I-a, I-c,I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d, III-e,or III-i, or as defined above.

In another embodiment of the present invention, R³ is H, F, Cl, CF₃,methyl or CN; and all other variables are as defined in Formula I, I-a,I-c, I-d, I-e, I-i, II-a, II-c, II-d, II-e, II-i, III-a, III-c, III-d,III-e, or III-i, or as defined above.

In an embodiment of the present invention, R⁴ is H, halo, CN, CF₃,—NR¹¹R¹², —OR¹¹, —SR¹¹, —C(═O)NR¹¹R¹², or C₁-C₆ alkyl, and all othervariables are as defined in Formula I, I-a, I-b, I-c, I-e, I-g, I-h,II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g,or III-h, or as defined above.

In another embodiment of the present invention, R⁴ is H, halo, CN, CF₃,—NR¹¹R¹² or —C(═O)NR¹¹R¹² wherein R¹¹ and R¹² are independently H orC₁-C₆ alkyl, —OR¹¹ wherein R¹¹ is H or C₁-C₆ alkyl, or —SR¹¹ wherein R¹¹is H or C₁-C₆ alkyl; and all other variables are as defined in FormulaI, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II -e, II-g, II-h,III-a, III-b, III-c, III-e, III-g, or III-h, or as defined above.

In another embodiment of the present invention, R⁴ is H, Br, CN, CF₃,—NH₂, —NH(CH₃), —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, —OH, or—OCH₃; and all other variables are as defined in Formula I, I-a, I-b,I-c, I-e, I-g, I -h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b,III-c, III-e, III-g, or III-h, or as defined above.

In another embodiment of the present invention, R⁴ is H, Br, Cl, CN,CF₃, —NH₂, —NH(CH₃), —N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, —OH,or —OCH₃; and all other variables are as defined in Formula I, I-a, I-b,I-c, I-e, I-g, I -h, II-a, II-b, II-c, II-e, II-g, II-h, III-a, III-b,III-c, III-e, III-g, or III-h, or as defined above.

In another embodiment of the present invention, R⁴ is halo, —OH, orC₁-C₆ alkyl optionally substituted by halo, and all other variables areas defined in Formula I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c,II-e, II-g, II-h, III-a, III-b, III-c, III-e, III-g, or III-h, or asdefined above.

In another embodiment of the present invention, R⁴ is independently Cl,Br, Me, Et, F, CHF₂, CF₃, or —OH; and all other variables are as definedin Formula I, I-a, I-b, I-c, I-e, I-g, I-h, II-a, II-b, II-c, II-e,II-g, II-h, III-a, III-b, III-c, III-e, III-g, or III-h, or as definedabove.

In an embodiment of the present invention, R⁵ is H or C₁-C₆ alkyl; andall other variables are as defined in Formula I, I-a to I-i, or II-a toII-i, or as defined above.

In another embodiment of the present invention, R⁵ is H or methyl; andall other variables are as defined in Formula I, I-a to I-i, or II-a toII-i, or as defined above.

In another embodiment of the present invention, R⁵ is H; and all othervariables are as defined in Formula I, I-a to I-i, or II-a to II-i, oras defined above.

In another embodiment of the present invention, R⁵ is methyl; and allother variables are as defined in Formula I, I-a to I-i, or II-a toII-i, or as defined above.

In an embodiment of the present invention, R⁶ is H or C₁-C₆ alkyl; andall other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, R⁶ is H or methyl; andall other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, R⁶ is H; and all othervariables are as defined in Formula I, I-a to I-i, II-a to II-i, orIII-a to III-i, or as defined above.

In another embodiment of the present invention, R⁶ is methyl; and allother variables are as defined in Formula I, I-a to I-i, II-a to II-i,or III-a to III-i, or as defined above.

In an embodiment of the present invention, X¹ is OR¹¹ (i.e., FormulaII-a to II-i); and all other variables are as defined in Formula I orI-a to I-i; or as defined above.

In an embodiment of the present invention, X¹ is OR¹¹ wherein R¹¹ is H;and all other variables are as defined in Formula I or I-a to I-i; or asdefined above.

In another embodiment of the present invention, X¹ is OR¹¹ wherein R¹¹is C₁-C₁₂ alkyl (e.g., C₁-C₆ alkyl) substituted with one or more groupsindependently selected from halo, CN, CF₃, —OCF₃, —NO₂, OXO, —Si(C₁-C₆alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and allother variables are as defined in Formula I or I-a to I-i, or as definedabove.

In another embodiment of the present invention, X¹ is:

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is OR¹¹ wherein R¹¹is heterocyclyl (e.g., 4- to 6-membered heterocyclyl) optionallysubstituted with one or more groups independently selected from halo,CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(C¹⁹R²⁰)_(n)S(O)(CR¹⁶)—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, X¹ is OR¹¹ wherein R¹¹is 4- to 6-membered heterocyclyl having 1 nitrogen ring atom whereinsaid heterocyclyl is optionally substituted with one or more groupsindependently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶)C(═Y)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, X¹ is

all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In an embodiment of the present invention, X¹ is R¹¹, and X¹ and R⁵ aretaken together with the nitrogen atom to which they are attached to forma 5-7 membered saturated or unsaturated cyclic ring having 0-2additional heteroatoms selected from O, S and N, wherein said cyclicring is optionally substituted with one or more groups selected fromhalo, CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl),—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), (CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, X¹ is R¹¹, and X¹ and R⁵are taken together with the nitrogen atom to which they are attached toform a 5-6 membered saturated cyclic ring having 0-2 additionalheteroatoms selected from O, S and N, wherein said cyclic ring isoptionally substituted with one or more groups selected from halo, CN,CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)—SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R¹⁹)_(n)OP(═Y²⁰)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶)—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, W is:

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, W is:

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, W is:

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In an embodiment of the present invention, X¹ is R¹¹, and X¹ and R⁵ aretaken together with the nitrogen atom to which they are attached to forma 4-membered saturated or unsaturated cyclic ring having 0-1 additionalheteroatoms selected from O, S and N, wherein said cyclic ring isoptionally substituted with one or more groups selected from halo, CN,CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)—SR¹⁶,—(CR¹⁹R₂₀)_(n)NR¹⁶C(═Y′)R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶, —(CR¹⁹R²⁰)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶)—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), (CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, W is:

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In an embodiment of the present invention, X¹ is —OR¹¹, and —OR¹¹ of X¹and R⁵ are taken together with the nitrogen atom to which they areattached to form a 4-7 membered saturated or unsaturated cyclic ringhaving 0-2 additional heteroatoms selected from O, S and N, wherein saidcyclic ring is optionally substituted with one or more groups selectedfrom halo, CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl),—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶),—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; andall other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In another embodiment of the present invention, X¹ is —OR¹¹, and —OR¹¹of X¹ and R⁵ are taken together with the nitrogen atom to which they areattached to form a 5-7 membered saturated or unsaturated cyclic ringhaving 0-2 additional heteroatoms selected from O, S and N, wherein saidcyclic ring is optionally substituted with one or more groups selectedfrom halo, CN, CF₃, —OCF₃, —NO₂, OXO, —Si(C₁-C₆ alkyl),—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶—(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷)—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷)—(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, X¹ is —OR¹¹, and —OR¹¹of X¹ and R⁵ are taken together with the nitrogen atom to which they areattached to form a 5-6 membered saturated cyclic ring having 0-2additional heteroatoms selected from O, S and N, wherein said cyclicring is optionally substituted with one or more groups selected fromhalo, CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl),—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶, (CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶)—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I or I-a to I-i, or as defined above.

In another embodiment of the present invention, W is:

and all other variables are as defined in Formula I or I-a to I-i, or asdefined above.

In an embodiment of the present invention, X¹ is R¹¹; and all othervariables are as defined in Formula I, I-a, I-b, I-c, I-d, I-e, I-f,I-g, I-h, or I-i, or as defined above.

In another embodiment of the present invention, X¹ is R¹¹ wherein R¹¹ isH; and all other variables are as defined in Formula I, I-a, I-b, I-c,I-d, I-e, I-f, I-g, I-h, or I-i, or as defined above.

In another embodiment of the present invention, X¹ is R¹¹ wherein R¹¹ isC₁-C₁₂ alkyl (e.g., C₁-C₆ alkyl) substituted with one or more groupsindependently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶SO₂R¹⁷,—(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)S(O)R¹⁶, —(CR¹⁹R²⁰)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶)—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷ and R²¹; and all other variables are asdefined in Formula I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, or I-i, oras defined above.

In another embodiment of the present invention, X¹ is

all other variables are as defined in Formula I, I-a, I-b, I-c, I-d,I-e, I-f, I-g, I-h, or I-i, or as defined above.

In another embodiment of the present invention, X¹ is

and all other variables are as defined in Formula I, I-a, I-b, I-c, I-d,I-e, I-f, I-g, I-h, or I-i, or as defined above.

In another embodiment of the present invention, X¹ is —S(O)₂R¹¹, and allother variables are as defined in Formula I, I-a, I-b, I-c, I-d, I-e,I-f, I-g, I-h, or I-i, or as defined above.

In another embodiment of the present invention, X¹ is —S(O)₂R¹¹ whereinR¹¹ is H or methyl; and all other variables are as defined in Formula I,I-a, I-b, I-c, I -d, I-e, I-f, I-g, I-h, or I-i, or as defined above.

In an embodiment of the present invention, W is —OR¹¹ (i.e., FormulaIII-a, II-b, III-c, III-d, III-e, III-f, III-g, III-h, or III-i) whereinR¹¹ of W is H or C₁-C₁₂ alkyl; and all other variables are as definedabove.

In another embodiment of the present invention, W is —OR¹¹ (i.e.,Formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, orIII-i) wherein R¹¹ of W is H; and all other variables are as definedabove.

In another embodiment of the present invention, W is —OR¹¹ (i.e.,Formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, orIII-i) wherein R¹¹ of W is C₁-C₆ alkyl; and all other variables are asdefined above.

In an embodiment of the present invention, X² is aryl (e.g., phenyl),wherein said aryl is optionally substituted with one or more groupsindependently selected from halo, CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)—SR¹⁶—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷)—(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)^(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or asdefined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or 111-a to III-i, or as defined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, X² is C₆-C₁₀ arylsubstituted with C₁-C₄ alkyl; and all other variables are as defined inFormula I, I-a to I-i, II-a to II-i, or III-a to III-i, or as definedabove.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

In another embodiment of the present invention, X² is carbocyclyl (e.g.,C₄-C₆ carbocyclyl) or heterocyclyl (e.g., 4- to 6-memberedheterocyclyl), wherein said carbocyclyl or heterocyclyl is optionallysubstituted with one or more groups independently selected from halo,CN, CF₃, —OCF₃, —NO₂, oxo, —Si(C₁-C₆ alkyl), —(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶, —(CR¹⁹R²⁰)_(n)—SR¹⁶,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷—(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶)—(CR¹⁹R²⁰)_(n)S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶,—(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; and all other variables are asdefined in Formula I, I-a to I-i, II-a to II-i, or III-a to III-i, or asdefined above.

In another embodiment of the present invention, X² is C₄-C₆ carbocyclylwherein said carbocyclyl is substituted with —C(═Y′)R¹⁶; and all othervariables are as defined in Formula I, I-a to I-i, II-a to II-i, orIII-a to III-i, or as defined above.

In another embodiment of the present invention, X² is

and all other variables are as defined in Formula I, I-a to I-i, II-a toII-i, or III-a to III-i, or as defined above.

Another embodiment of the present invention includes compounds describedin EXAMPLES 5-12 and compounds below:

The present compounds are prepared according to the procedures describedbelow in the schemes and examples or by methods known in the art. Thestarting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available compounds, orprepared using well known synthetic methods (for example, thosedescribed in WO02/06213, WO 03/077855 and WO03/077914).

For example, 5-azabenzothiophenes of Formula (I-b), (II-b) or (III-b)may be prepared using the synthetic routes outlined in Schemes 1, 2 and3.

Compounds of formula (IV) may be prepared using published methodsdescribed in the literature. They may be reacted with methylthioglycolate or ethyl thioglycolate in the presence of a base, such assodium hydride, in a suitable solvent, such as N,N-dimethylformamide or1,2-dimethoxyethane, at a temperature of from −50° C. to roomtemperature, to obtain compounds of formula (VI).

Compounds of formula (VI) may be converted to compounds of formula (VII)by reaction with a halogenating agent such as phosphorus oxybromide,neat or in a suitable solvent such as toluene, at a temperature of fromroom temperature to 140° C. Alternatively, compounds of formula (VI) maybe reacted with nonafluorobutane sulphonyl fluoride in the presence of abase such as diisopropylethylamine and a catalyst such asN,N-dimethyl-4-aminopyridine, in a solvent such as dichloromethane atroom temperature, with N-phenyltrifluoromethanesulfonimide in thepresence of a base such as diisopropylethylamine, in a suitable solventsuch as 1,2-dimethoxyethane at a temperature from room temperature tothe reflux temperature of the solvent. In addition, compounds of formula(VI) may be treated with trifluoromethanesulphonic acid anhydride in thepresence of a base such as pyridine in a solvent such as dichloromethaneat a temperature of from −20° C. to ambient temperature.

Compounds of formula (VIII) may be obtained from compounds of formula(VII) by reaction with an aniline (incorporating appropriatesubstituents R1), in the presence of a catalyst such astris(dibenzylideneacetone)dipalladium (0) or palladium acetate, a basesuch as potassium phosphate, sodium tert-butoxide,1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, a ligand such as9,9′-dimethyl-4,5-bis(diphenylphosphino)xanthene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,6′-(dimethoxy)biphenyl or tri-butyl-phosphinein a suitable solvent such as toluene, 1,2-dimethoxyethane,tetrahydrofuran or dioxane, at a temperature of from room temperature tothe reflux temperature of the solvent, or under microwave irradiation ata temperature of from 70° C. to 150° C.

Alternatively compounds of formula (VIII) can be obtained from compoundsof formula (VI) by reaction with compounds of formula (IX) (preparedusing published methods described in the literature), in a suitablesolvent such as toluene or 1,2-dimethoxyethane, at a temperature of fromroom temperature to the reflux temperature of the solvent, or undermicrowave irradiation at a temperature of from 100° C. to 180° C.

Compounds of formula (X) can be obtained from compounds of formula (VIf)by reaction with a base such as sodium hydroxide in a protic solventsuch as ethanol or methanol, at a temperature of from room temperatureup to reflux temperature.

Compounds of formula (X) can be reacted with a functionalisedhydroxylamine of formula (XII) (commercially available or preparedaccording to Scheme 6) or an amine, and a suitable coupling agent, suchas O-(7-aza-benzo-triazol -1-yl)-N,N,N′,N′-tetra-methyluronium hexafluoro-phosphate, N-(3-dimethylaminopropyl) -N′-ethylcarbodiimidehydrochloride or N,N′-dicyclohexylcarbodiimide in the presence ofN-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base suchas diisopropylethylamine or triethylamine in an inert solvent, such astetrahydrofuran, NAN -dimethylformamide, or dichloromethane at atemperature of about room temperature, to obtain the compounds offormula (XI). Alternatively, compounds of formula (XI) can be obtaineddirectly from compounds of formula (VIII) by reaction with an amine orhydroxylamine DNHR in the presence of a Lewis acid such as trimethylaluminium in a solvent such as DCM, at a temperature of from roomtemperature up to reflux temperature.

Alternatively, compounds of formula (VIII) can be prepared fromcompounds of formula (XII), according to Scheme 2.

Compounds of formula (XIII) may be prepared using published methodsdescribed in the literature. Compounds of general formula (XIV) can beprepared from compounds of formula (XIII) using methods described abovefor the preparation of compounds of formula (VI) from compounds offormula (IV).

Compounds of formula (VI) may be obtained from compounds of formula(XIV) by reaction with compounds of formula (XV) (incorporatingappropriate substituents R1), using methods described above for thepreparation of compounds of formula (VI) from compounds of formula (VI).Alternatively, compounds of formula (VIII) may be obtained fromcompounds of formula (XIV) by reaction with compounds of formula (XVI)(incorporating appropriate substituents R1), in the presence of a basesuch as sodium hydride or lithium hexamethyldisilazane, in a suitablesolvent such as tetrahydrofuran or N,N-dimethylformamide, at atemperature of from room temperature to 150° C.

Alternatively, compounds of formula (X) can also be prepared fromcompounds of formula (VII) according to Scheme 3.

Compounds of formula (VII) can be converted to compounds of formula(XVII) using methods described above for the preparation of compounds offormula (X) from compounds of formula (VIII). Compounds of formula(XVII) can be coupled to amines such as 2-amino-2-methyl-1-propanolusing methods described above for the preparation of compounds offormula (XI) from compounds of formula (X), followed by reaction with anagent such as thionyl chloride or phosphorus oxychloride, neat or in asuitable solvent such as dichloromethane, chloroform or diethyl ether,at a temperature of from room temperature to reflux of the solvent, toafford compounds of formula (XVIII).

Compounds of formula (XIX) may be obtained from compounds of formula(XVIII) by reaction with an aniline (incorporating appropriatesubstituents R1), in the presence of a catalyst such astris(dibenzylideneacetone)dipalladium (0) or palladium acetate, a basesuch as potassium phosphate, sodium tert-butoxide,1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, a ligand such as9,9′-dimethyl-4,5-bis(diphenylphosphino)xanthene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,6′-(dimethoxy)biphenyl or tri-butyl-phosphinein a suitable solvent such as toluene, 1,2-dimethoxyethane,tetrahydrofuran or dioxane, at a temperature of from room temperature tothe reflux temperature of the solvent, or under microwave irradiation ata temperature of from 70° C. to 150° C.

Alternatively, compounds of formula (XIX) may be obtained from compoundsof formula (XVIII) by reaction with compounds of anilines (incorporatingappropriate substituents R1), in the presence of a base such as sodiumhydride or lithium hexamethyldisilazane, in a suitable solvent such astetrahydrofuran or N,N-dimethylformamide, at a temperature of from roomtemperature to 150° C. Compounds of formula (X) may be obtained fromcompounds of formula (XIX) by reaction with an acid such as hydrogenchloride, or acetic acid in a suitable solvent such as water, at atemperature of from room temperature to reflux of the solvent.

6-Azabenzothiophenes of Formula I-c, II-c or III-c may be prepared usingthe synthetic routes outlined in Scheme 4.

Compounds of formula (XX) may be prepared using published methodsdescribed in the literature. They may be reacted with methyl glycolateor ethyl glycolate in the presence of a phosphine such as triphenylphosphine, an alkyl-azodicarboxylate such as diethyl azodicarboxylate ordiisopropyl azodicarboxylate, in an aprotic solvent, such astetrahydrofuran or diethyl ether, at a temperature of from roomtemperature to reflux of the solvent, to obtain compounds of formula(XXI).

Compounds of formula (XXI) may be reacted in the presence of a base,such as sodium hydride, in a suitable solvent, such asN,N-dimethylformamide or 1,2-dimethoxyethane, at a temperature of from−50° C. to room temperature, to obtain compounds of formula (XXII).

Compounds of formula (XXII) may be converted to compounds of formula(XXIII) by reaction with a halogenating agent such as phosphorusoxybromide, neat or in a suitable solvent such as toluene, at atemperature of from room temperature to 140° C. Alternatively, compoundsof formula (XXII) may be reacted with nonafluorobutane sulphonylfluoride in the presence of a base such as diisopropylethylamine and acatalyst such as N,N-dimethyl-4-aminopyridine, in a solvent such asdichloromethane at room temperature, withN-phenyltrifluoromethanesulfonimide in the presence of a base such asdiisopropylethylamine, in a suitable solvent such as 1,2-dimethoxyethaneat a temperature from room temperature to the reflux temperature of thesolvent. In addition compounds of formula (VI) may be treated withtrifluoromethanesulphonic acid anhydride in the presence of a base suchas pyridine in a solvent such as dichloromethane at a temperature offrom −20° C. to ambient temperature.

Compounds of formula (XXIV) may be obtained from compounds of formula(XXI) by reaction with an aniline (incorporating appropriatesubstituents R1), in the presence of a catalyst such astris(dibenzylideneacetone)dipalladium (0) or palladium acetate, a basesuch as potassium phosphate, sodium tert-butoxide,1,8-diazabicyclo[5.4.1]undec-7-ene or cesium carbonate, a ligand such as9,9′-dimethyl-4,5-bis(diphenylphosphino)xanthene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,6′-(dimethoxy)biphenyl or tri-butyl-phosphinein a suitable solvent such as toluene, 1,2-dimethoxyethane,tetrahydrofuran or dioxane, at a temperature from room temperature tothe reflux temperature of the solvent, or under microwave irradiation ata temperature of from 70° C. to 150° C.

Alternatively compounds of formula (XXIV) can be obtained from compoundsof formula (XXII) by reaction with compounds of formula (IX) (preparedusing published methods described in the literature), in a suitablesolvent such as toluene or 1,2-dimethoxyethane, at a temperature fromroom temperature to the reflux temperature of the solvent, or undermicrowave irradiation at a temperature of from 100° C. to 180° C.

Compounds of formula (XXVI) can be obtained from compounds of formula(XXIV) by reaction with a base such as sodium hydroxide in a prpticsolvent such as ethanol or methanol, at a temperature from roomtemperature up to reflux temperature.

Compounds of formula (XXVI) can be reacted with a functionalisedhydroxylamine of formula (XII) (commercially available or preparedaccording to Scheme 6) or an amine, and a suitable coupling agent, suchas O-(7-aza-benzo-triazol -1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluoro-phosphate, N-(3-dimethylaminopropyl) -N′-ethylcarbodiimidehydrochloride or N,N′-dicyclohexylcarbodiimide in the presence ofN-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base suchas diisopropylethylamine or triethylamine in an inert solvent, such astetrahydrofuran, N,N -dimethylformamide, or dichloromethane at atemperature of about room temperature, to obtain the compounds offormula (XXVII). Alternatively, compounds of formula (XXVI) can beobtained directly from compounds of formula (XXIV) by reaction with anamine or hydroxylamine DNHR in the presence of a Lewis acid such astrimethyl aluminium, in a solvent such as DCM, at a temperature of fromroom temperature up to reflux temperature.

Thieno[2,3-d]pyrimidines of Formula I-f, II-f or III-f may be preparedusing the synthetic routes outlined in Scheme 5.

Compounds of formula (XXVIII) may be prepared according to methodsdescribed in the literature. They may reacted with a halogenating agentsuch as phosphorus oxychloride, neat or in a suitable solvent such astoluene, at a temperature from room temperature to reflux, to providecompounds of formula (XXIX).

Compounds of formula (XXXVI) may be obtained from compounds of formula(XXIX) using similar methods to the ones described for the preparationof compounds of formula (XI) from compounds of formula (IV), as shown inScheme 5.

Hydroxylamines of formula (XII) may be prepared using methods describedin the literature or the synthetic route outlined in Scheme 6.

Primary or secondary alcohols of general formula (XXXVII) may beprepared using methods described in the literature. They may be reactedwith 1-hydroxy phthalimide using a phosphine and coupling reagent suchas diethyl azodicarboxylate to provide compounds of general formula(XXXVIII). Compounds of general formula (XXXVIII) may be deprotectedusing hydrazine or methyl hydrazine to provide hydroxylamines of generalformula (XII-a). Compounds of formula (XII-a) may be further modified byreductive amination with aldehydes or ketones using a reducing agentsuch as sodium triacetoxy borohydride, sodium cyanoborohydride, orborane-pyridine in a solvent such as dichloroethane at a temperature offrom ambient temperature to reflux. In addition, compounds of formula(XII-a) may be further modified by alkylation with an alkyl halide inthe presence of a base such as triethylamine, in a solvent such asdichloromethane, to provide hydroxylamines of general formula (XII-b).

Anilines of general formula (XXXIX) used in cross-coupling reactionsdescribed above may be prepared by using methods described in theliterature or according to Scheme 7.

Substituted 4-chloro-nitro benzene may be reacted withhexamethyldisilane in a solvent such as xylene using a catalyst such astetrakis(triphenylphosphine)palladium at a temperature of from roomtemperature to reflux. The nitro group may be reduced using methodsdescribed in the literature such as reaction under an atmosphere ofhydrogen at a pressure of from 1 to 5 atmospheres in the presence of acatalyst such as palladium on carbon and in a solvent such as ethanol orethyl acetate at room temperature.

Trifluoromethanesulfonyl esters of general formula (XL) used incross-coupling reactions described above may be prepared by usingmethods described in the literature or according to Scheme 8.

Halo phenols of general structure (XLI) may be reacted with twoequivalents of alkylithium reagents such as n-butyl lithium in a solventsuch as THF, followed by quenching with trialkylsilyl halide such astrimethylsilyl chloride to give trialkylsilyl phenols (XLII).Trialkylsilyl phenols may be further reacted using literature proceduresto give trifluoromethane sulfonates or nonaflates of general structure(XL)

It will be appreciated that where appropriate functional groups exist,compounds of formula (I), (II), (III) or any intermediates used in theirpreparation may be further derivatised by one or more standard syntheticmethods employing substitution, oxidation, reduction, or cleavagereactions. Particular substitution approaches include conventionalalkylation, arylation, heteroarylation, acylation, sulfonylation,halogenation, nitration, formylation and coupling procedures.

For example, aryl bromide or chloride groups may be converted to aryliodides using a Finkelstein reaction employing an iodide source such assodium iodide, a catalyst such as copper iodide and a ligand such astrans-N,N′-dimethyl-1,2-cyclohexane diamine in a solvent such as1,4-dioxane and heating the reaction mixture at reflux temperature. Aryltrialkylsilanes may be converted to aryl iodides by treating the silanewith an iodide source such as iodine monochloride in a solvent such asdichloromethane with or without Lewis acid such as silvertetrafluoroborate at a temperature from −40° C. to reflux.

In a further example primary amine (—NH₂) groups may be alkylated usinga reductive alkylation process employing an aldehyde or a ketone and aborohydride, for example sodium triacetoxyborohydride or sodiumcyanoborohydride, in a solvent such as a halogenated hydrocarbon, forexample 1,2-dichloroethane, or an alcohol such as ethanol, wherenecessary in the presence of an acid such as acetic acid at aroundambient temperature. Secondary amine (—NH—) groups may be similarlyalkylated employing an aldehyde.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCOR′ or —NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriate carboxylic acidin the presence of a suitable coupling agent such HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulphonamide groups(—NHSO₂R′ or —NR″SO₂R′) groups by reaction with an appropriate sulphonylchloride in the presence of a suitable base, such as triethylamine, in asuitable solvent such as dichloromethane. Primary or secondary aminegroups can be converted into urea groups (—NHCONR′R″ or —NRCONR′R″) byreaction with an appropriate isocyanate in the presence of a suitablebase such as triethylamine, in a suitable solvent, such asdichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g. tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CN), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, ata temperature from −78° C. to the reflux temperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CN) using diisobutylaluminium hydride in asuitable solvent such as toluene. Alternatively, aldehyde groups may beobtained by the oxidation of alcohol groups using any suitable oxidisingagent known to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalused hydrolysis, depending on the natureof R. If R is t-butyl, acid-catalysed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CO₂H) may be converted into amides (CONHR′ or—CONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e —CO₂H to —CH₂CO₂H) by conversion to the corresponding acid chloride(—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g. —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminium hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminium hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxygroup using conditions known to those skilled in the art. For example,an alcohol may be reacted with thioyl chloride in a halogenatedhydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.A base (e.g. triethylamine) may also be used in the reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl-, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g. sodium hydride followed bysubsequent addition of an alkylating agent, such as an alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g. palladium orcopper) catalysed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteraryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

The compounds of the present invention are tested for their capacity toinhibit MEK activity and activation (primary assays) and for theirbiological effects on growing cells (secondary assays) as describedbelow. The compounds having IC₅₀ of less than 10 μM (more preferablyless than 5 μM, even more preferably less than 1 μM, most preferablyless than 0.5 μM) in the MEK activity assay of Example 1a or 1b, IC₅₀ ofless than 5 μM (more preferably less than 0.1 μM, most preferably lessthan 0.01 μM) in the MEK activation assay of Example 2, EC₅₀ of lessthan 10 μM (more preferably less than 5 μM, most preferably less than0.5 μM) in the cell proliferation assay of Example 3, and/or EC₅₀ ofless than 10 μM (more preferably less than 1 μM, most preferably lessthan 0.1 μM) in the ERK phosphorylation assay of Example 4, are usefulas MEK inhibitors.

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of Formula I (and/or solvates andsalts thereof) and a carrier (a pharmaceutically acceptable carrier).The present invention also includes a composition (e.g., apharmaceutical composition) comprising a compound of Formula I (and/orsolvates and salts thereof) and a carrier (a pharmaceutically acceptablecarrier), further comprising a second chemotherapeutic agent and/or asecond anti-inflammatory agent such as those described herein. Thepresent compositions are useful for inhibiting abnormal cell growth ortreating a hyperproliferative disorder in a mammal (e.g., human). Thepresent compositions are also useful for treating inflammatory diseasesin a mammal (e.g., human).

The present compounds and compositions are also useful for treating anautoimmune disease, destructive bone disorder, proliferative disorders,infectious disease, viral disease, fibrotic disease or neurodegenerativedisease in a mammal (e.g., human). Examples of such diseases/disordersinclude, but are not limited to, diabetes and diabetic complications,diabetic retinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis andatopic dermatitis, renal disease and renal failure, polycystic kidneydisease, congestive heart failure, neurofibromatosis, organ transplantrejection, cachexia, stroke, septic shock, heart failure, organtransplant rejection, Alzheimer's disease, chronic or neuropathic pain,and viral infections such as HIV, hepatitis (B) virus (HBV), humanpapilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus(EBV). Chronic pain, for purposes of the present invention includes, butis not limited to, idiopathic pain, and pain associated with chronicalcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation,arthritis, and post-operative pain. Neuropathic pain is associated withnumerous conditions which include, but are not limited to, inflammation,postoperative pain, phantom limb pain, burn pain, gout, trigeminalneuralgia, acute herpetic and postherpetic pain, causalgia, diabeticneuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crushinjury, constriction injury, tissue injury, limb amputation, arthritispain, and nerve injury between the peripheral nervous system and thecentral nervous system.

The present compounds and compositions are also useful for treatingpancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) in a mammal(e.g., human).

The present compounds and compositions are also useful for theprevention of blastocyte implantation in a mammal (e.g., human).

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I (and/or solvates and saltsthereof) or a composition thereof. Also included in the presentinvention is a method of treating an inflammatory disease in a mammal(e.g., human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I (and/or solvates and/orsalts thereof) or a composition thereof.

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I (and/or solvates and saltsthereof) or a composition thereof, in combination with a secondchemotherapeutic agent such as those described herein. The presentinvention also includes a method of treating an inflammatory disease ina mammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I (and/orsolvates and/or salts thereof) or a composition thereof, in combinationwith a second anti-inflammatory agent such as those described herein.

The present invention includes a method of treating an autoimmunedisease, destructive bone disorder, proliferative disorders, infectiousdisease, viral disease, fibrotic disease or neurodegenerative disease ina mammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I (and/orsolvates and salts thereof) or a composition thereof, and optionallyfurther comprising a second therapeutic agent. Examples of suchdiseases/disorders include, but are not limited to, diabetes anddiabetic complications, diabetic retinopathy, retinopathy ofprematurity, age-related macular degeneration, hemangioma, idiopathicpulmonary fibrosis, rhinitis and atopic dermatitis, renal disease andrenal failure, polycystic kidney disease, congestive heart failure,neurofibromatosis, organ transplant rejection, cachexia, stroke, septicshock, heart failure, organ transplant rejection, Alzheimer's disease,chronic or neuropathic pain, and viral infections such as HIV, hepatitis(B) virus (HBV), human papillomna virus (HPV), cytomegalovirus (CMV),and Epstein-Barr virus (EBV).

The present invention includes a method of treating pancreatitis orkidney disease (including proliferative glomerulonephritis anddiabetes-induced renal disease) in a mammal (e.g., human) comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula I (and/or solvates and salts thereof) or acomposition thereof, and optionally further comprising a secondtherapeutic agent.

The present invention includes a method for preventing of blastocyteimplantation in a mammal (e.g., human) comprising administering to saidmammal a therapeutically effective amount of a compound of Formula I(and/or solvates and salts thereof) or a composition thereof, andoptionally further comprising a second therapeutic agent.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or associated pathological conditions.

It is also believed that the compounds of the present invention canrender abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal (e.g., human) to treatment with radiationwhich comprises administering to said mammal an amount of a compound ofFormula I (and/or solvates and salts thereof) or a composition thereof,which amount is effective is sensitizing abnormal cells to treatmentwith radiation.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, inhalation and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied asia sole therapy or in combinationwith one or more chemotherapeutic agents, for example those describedherein. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof treatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES Abbreviations

-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCM Dichloromethane-   DIPEA Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DMF Dimethylformamide-   EDCI 1-Ethyl-3-(3′-dimethylaminopropyl)carbddiimide-   HATU O-(7-Azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   HM-N Isolute® HM-N is a modified form of diatomaceous earth that can    efficiently absorb aqueous samples-   HOBt 1-Hydroxybenzotriazole-   LDA Lithium diisopropylamide-   MeOH Methanol-   NaHCO₃ Sodium bicarbonate-   NaOH Sodium hydroxide-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-   Pd₂ dba₃ Tris-(dibenzylideneacetone)dipalladium(0)-   PdCl₂(PPh₃)₂ Dichlorobis(triphenylphosphine)palladium(II)-   Si-SPE Pre-packed Isolute® silica flash chromatography cartridge-   THF Tetrahydrofuran-   Xantphos 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene

General Experimental Conditions

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probe.Chemical shifts are expressed in ppm relative to tetramethylsilane. Thefollowing abbreviations have been used: br=broad signal, s=singlet,d=doublet, dd=double doublet, t=triplet, q=quartet, m=multiplet.

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (R_(T)) and associated mass ions wereperformed using one of the following methods.

Method A: Experiments performed on a Waters Micromass ZQ quadrupole massspectrometer linked to a Hewlett Packard HPI 100 LC system with diodearray detector. Uses a Higgins Clipeus 5 micron C18 100×3.0 mm columnand a 1 ml/minute flow rate. The initial solvent system was 95% watercontaining 0.1% formic acid (solvent A) and 5% acetonitrile containing0.1% formic acid (solvent B) for the first minute followed by a gradientup to 5% solvent A and 95% solvent B over the next 14 minutes. The finalsolvent system was held constant for a further 5 minutes.

Method B: Experiments performed on a Waters Platform LC quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system with diodearray detector and 100 position autosampler using a Phenomenex LunaC18(2) 30×4.6 mm column and a 2 ml/minute flow rate. The solvent systemwas 95% solvent A and 5% solvent B for the first 0.50 minutes followedby a gradient up to 5% solvent A and 95% solvent B over the next 4minutes. The final solvent system was held constant for a further 0.50minutes.

Microwave experiments were carried out using a Personal Chemistry EmrysInitiator™ or Optimizer™, which uses a single-mode resonator and dynamicfield tuning, both of which give reproducibility and control.Temperature from 40-250° C. can be achieved, and pressures of up to 20bar can be reached.

Example 1a MEK Assay MEK activity Assay

Constitutively activated human mutant MEK1 expressed in insect cells isused as source of enzymatic activity at a final concentration in thekinase assay of 62.5 nM.

The assay is carried out for 30 minutes in the presence of 50 μM ATPusing recombinant GST-ERK1 produced in E. Coli as substrate.Phosphorylation of the substrate is detected and quantified using HTRFreagents supplied by Cisbio. These consist of an anti-GST antibodyconjugated to allophycocyanin (XL665) and an anti-phospho(Thr202/Tyr204) ERK antibody conjugated to europium-cryptate. Theanti-phospho antibody recognises ERK1 dually phosphorylated on Thr202and Tyr204. When both antibodies are bound to ERK1 (i.e. when thesubstrate is phosphorylated), energy transfer from the cryptate to theallophycocyanin occurs following excitation at 340 nm, resulting influorescence being emitted that is proportional to the amount ofphosphorylated substrate produced. Fluorescence is detected using amultiwell fluorimeter.

Compounds are diluted in DMSO prior to addition to assay buffer and thefinal DMSO concentration in the assay is 1%.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

Example 1b MEK Assay MEK activity Assay

Constitutively activated human mutant MEK1 expressed in insect cells isused as source of enzymatic activity at a final concentration in thekinase assay of 15 nM.

The assay is carried out for 30 minutes in the presence of 50 μM ATPusing recombinant GST-ERK1 produced in E. Coli as substrate.Phosphorylation of the substrate is detected and quantified using HTRFreagents supplied by Cisbio. These consist of an anti-GST antibodyconjugated to allophycocyanin (XL665) and an anti-phospho(Thr202/Tyr204) ERK antibody conjugated to europium-cryptate. These areused at a final concentration of 4 μg/ml and 0.84 μg/ml respectively.The anti-phospho antibody recognises ERK1 dually phosphorylated onThr202 and Tyr204. When both antibodies are bound to ERK1 (i.e. when thesubstrate is phosphorylated), energy transfer from the cryptate to theallophycocyanin occurs following excitation at 340 nm, resulting influorescence being emitted that is proportional to the amount ofphosphorylated substrate produced. Fluorescence is detected using amultiwell fluorimeter.

Compounds are diluted in DMSO prior to addition to assay buffer and thefinal DMSO concentration in the assay is 1%.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

Compounds of Examples 5-8 and 10-12 exhibited an IC₅₀ of less than 10 μMin the assay described either in Example 1a or 1b, most of thesecompounds exhibited an IC₅₀ of less than 5 μM.

Example 2 bRaf Assay MEK Activation Assay

Constitutively activated bRaf mutant expressed in insect cells is usedas source of enzymatic activity.

The assay is carried out for 30 minutes in the presence of 200 μM ATPusing recombinant GST-MEK1 produced in E. Coli as substrate.Phosphorylation of the substrate is detected and quantified using HTRF,and reagents are supplied by Cisbio. These consist of an anti-GSTantibody conjugated to allophycocyanin (XL665) and an anti-phosphol(Ser217/Ser221) MEK antibody conjugated to europium-cryptate. The anti-phospho antibody recognises MEK dually phosphorylated on Ser217 andSer221 or singly phosphorylated on Ser217. When both antibodies arebound to MEK (i.e. when the substrate is phosphorylated), energytransfer from the cryptate to the allophycocyanin occurs followingexcitation at 340 nm, resulting in fluorescence being emitted that isproportional to the amount of phosphorylated substrate produced.Fluorescence is detected using a multiwell fluorimeter.

Compounds are diluted in DMSO prior to addition to assay buffer and thefinal DMSO concentration in the assay is 1%.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

In this assay, compounds of Examples 5-7 and 10 exhibited an IC₅₀ ofless than 5 μM.

Example 3 Cell Proliferation Assay

Compounds are tested in a cell proliferation assay using the followingcell lines:

HCT116 human colbrectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines are maintained in DMEMIF12 (1:1) media (Gibco)supplemented with 10% FCS at 37° C. in a 5% CO₂ humidified incubator.

Cells are seeded in 96-well plates at 2,000 cells/well and after 24hours they are exposed to different concentrations of compounds in 0.83%DMSO. Cells are grown for a further 72 h, and an equal volume ofCellTiter-Glo reagent (Promega) is added to each well. This lyses thecells and generates a luminescent signal proportional to the amount ofATP released (and therefore proportional to the number of cells in thewell) that can be detected using a multiwell luminometer.

The EC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. EC₅₀ values are calculated using theXLfit software package (version 2.0.5).

In this assay, compounds of Examples 5 and 10 exhibited an EC₅₀ of lessthan 10 μM in either one of the cell lines.

Example 4 Phospho-ERK Cell-Based Assay

Compounds are tested in a cell-based phospho-ERK ELISA using thefollowing cell lines:

HCT116 human colorectal carcinoma (ATCC)

A375 human malignant melanoma (ATCC)

Both cell lines are maintained in DMEM/F12 (1:1) media (Gibco)supplemented with 10% FCS at 37° C. in a 5% CO₂ humidified incubator.

Cells are seeded in 96-well plates at 2,000 cells/well and after 24 hthey are exposed to different concentrations of compounds in 0.83% DMSO.Cells are grown for a further 2 h or 24 h, fixed with formaldehyde (2%final) and permeabilised with methanol. Following blocking with TBST-3%BSA, fixed cells are incubated with primary antibody (anti-phospho ERKfrom rabbit) over-night at 4° C. Cells are incubated with PropidiumIodide (DNA fluorescent dye) and detection of cellular p-ERK isperformed using an anti-rabbit secondary antibody conjugated to thefluorescent Alexa Fluor 488 dye (Molecular probes). The fluorescence isanalysed using the Acumen Explorer (lTP Labtech), a laser-scanningmicroplate cytometer, and the Alexa Fluor 488 signal is normalised tothe PI signal (proportional to cell number).

The EC₅₀ is defined as the concentration at which a given compoundachieves a signal half way between the baseline and the maximumresponse. EC₅₀ values are calculated using the XLfit software package(version 2.0.5).

In this assay, compounds of Examples 5 and 10-12 exhibited an EC₅₀ ofless than 10 μM in either one of the cell lines.

Example 5 4-Chloro-nicotinic acid

Following the procedures of Guillier et al (1995) J. Org. Chem.60(2):292-6, to a cold (−78° C.) solution of LDA (21 ml, 1.6 M inhexanes, 33.3 mmol) in anhydrous THF (70 ml) was added 4-chloropyridine(5.0 g, 33.3 mmol) under an argon atmosphere. After 1 hour at −78° C.,the solution was rapidly poured onto a bed of solid CO₂ contained withina 250 ml conical flask. After allowing the reaction solution to warm toambient temperature the solution was quenched with water (30 ml). Thevolatile organic solvents were removed in vacuo and the remainingaqueous suspension was extracted with diethyl ether (3×100 ml). Theaqueous phase was cooled to 0° C. and the adjusted to pH 4 by theaddition of concentrated hydrochloric acid. The resultant precipitatewas aged for 30 minutes then collected by filtration. The solid waswashed with cold diethyl ether (10 ml) to afford the title compound as awhite solid (3.2 g, 61%).

Ethyl 4-chloro-nicotinate

A suspension of 4-chloro-nicotinic acid (3.0 g, 19.0 mmol) in thionylchloride (50 ml) was heated under reflux for 90 minutes. After coolingto ambient temperature, the solution was concentrated to dryness andthen azeotroped with toluene (2×50 ml) to afford a solid. The resultantsolid was added in portions to a cooled (0° C.) solution of ethanol (25ml) and DIPEA (15 ml). The reaction was stirred at room temperature for4 hours then concentrated in vacuo before water (75 ml) was added. Thesolution was extracted with ethyl acetate (2×75 ml) then the combinedorganic phases were dried over sodium sulfate then concentrated to givethe title compound as a brown oil (3.3 g, 94%). ¹H NMR (CDCl₃, 400 MHz)9.03 (s, 1H), 7.58 (d, J=5.4 Hz, 1H), 7.41 (dd, J=5.4 Hz, 0.5 Hz, 1H),4.45 (q, J=7.3 Hz, 2H), 1.43 (t, J=7.3 Hz, 3H).

3-Hydroxy-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester

To a cooled (5° C.) stirred solution of ethyl 4-chloro-nicotinate (1.55g, 8.4 mmol) and mercapto-acetic acid ethyl ester (2.6 ml, 23.4 mmol) inanhydrous DMF (30 ml), under an argon atmosphere, was added sodiumhydride (21.7 mmol; 60% dispersion in oil, 868 mg) in portions over 20minutes. Stirring was continued at 5° C. for 10 minutes, followed by 1.5hours at room temperature. The reaction mixture was then quenched by theaddition of water (5 ml), acidified by the addition of acetic acid (1ml), and subsequently concentrated to provide a residue. The residue waspartitioned between ethyl acetate (150 ml) and water (100 ml). Thelayers were separated and aqueous phase was extracted with DCM (100 ml).The combined organic phase was dried over sodium sulphate, filtered andevaporated to give a solid. The solid was triturated with diethylether:pentane (1:1, 15 ml) to afford the title compound as a yellowsolid (1.5 g, 81%). LCMS (method B): R_(T)=2.21 min, M+H⁺=224.

3-(Nonafluorobutane-1-sulfonyloxy)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester

To a stirred solution of 3-hydroxy-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester (1.3 g, 5.82 mmol) and DMAP (35 mg, 0.29 mmol) in DCM(10 ml) at 0° C. was added DIPEA (2.5 ml, 14.0 mmol) andnonafluorobutylsulfonyl fluoride (1.36 ml, 7.56 mmol). After 10 minutesthe reaction mixture was warmed to room temperature and stirred for anadditional 20 hours. The reaction mixture was diluted with DCM (50 ml)and washed with water (30 ml). The organic phase was isolated, driedover sodium sulphate, filtered and evaporated to give a brown oil. Theoil was purified by flash chromatography (Si-SPE, pentane:diethyl ether,gradient 100:0 to 70:30) to afford the title compound as a colourlessoil which crystallised on standing (420 mg, 14%). LCMS (method B):R_(T)=4.46 min, M+H⁺=508.

3-(4-Bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acidethyl ester

A degassed solution of3-(nonafluorobutane-1-sulfonyloxy)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester (422 mg, 0.83 mmol), 4bromo -2-fluoroaniline (206 mg,1.08 mmol), Pd₂ dba₃ (38 mg, 0.04 mmol), Xantphos (48 mg, 0.08 mmol) andDBU (316 μl, 2.08 mmol) in toluene (1 ml) was subjected to microwaveirradiation at 150° C. for 10 minutes. The reaction mixture was cooledto ambient temperature then diluted with ethyl acetate (30 ml). Theresultant solution was washed with water (20 ml), dried over sodiumsulfate and concentrated in vacuo to give a solid residue. The solidresidue was purified by flash chromatography (Si-SPE, pentane:diethylether, gradient 90:10 to 70:30) to afford the title compound as a whitesolid (210 mg, 64%). LCMS (method B): R_(T)=3.78 min, M+H⁺=395/397.

3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acidethyl ester

A mixture of3-(4-bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acidethyl ester (209 mg, 0.53 mmol), copper (1) iodide (5 mg, 0.026 mmol),sodium iodide (159 mg, 1.06 mmol) andtrans-N,N′-dimethyl-1,2-cyclohexane diamine (8.5 g, 0.053 mmol) in1,4-dioxane (1.0 ml) was heated at 105° C. for 24 hours under an argonatmosphere. Copper (1) iodide (5 mg, 0.026 mmol) andtrans-N,N′-dimethyl-1,2-cyclohexane diamine (8.5 μl, 0.053 mmol) wereadded and heating continued for a further 24 h. Once the reaction wascooled to room temperature, the mixture was partitioned between ethylacetate (30 ml) and 10% v/v 0.880 ammonia/water (20 ml). The layers wereseparated and the aqueous phase was extracted with DCM (30 ml). Thecombined organic layer was dried over sodium sulphate, filtered andevaporated then the residue was purified by flash chromatography aSi-SPE (eluting with pentane:diethyl ether, gradient 90:10 to 70:30) toafford the title compound as a yellow solid (174 mg, 74%). LCMS (methodB): R_(T)=3.97 min, M+H⁺=443.

3-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

A mixture of3-(2-fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acidethyl ester (50 mg, 0.11 mmol), 1N aqueous NaOH solution (0.12 ml, 0.12mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. Thereaction mixture was concentrated then azeotroped with toluene (2×2 ml)to give a solid residue. The solid residue was dissolved in anhydrousTHF (2 ml) andO—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (27 mg, 0.23mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59μl, 0.34 mmol) were added. After stirring for 19 hours the solvent wasevaporated and the residue partitioned between ethyl acetate (30 ml) andwater (20 ml). The organic layer was dried over sodium sulphate,filtered and evaporated to give a yellow oil. The oil was purified byflash chromatography (Si-SPE, pentane:ethyl acetate, gradient 80:20 to50:50) to afford the title compound as a yellow solid (18 mg, 30%). LCMS(method B): R_(T)=3.09 min, M+H⁺=544.

3-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid((R)-2,3-dihydroxy-propoxy)-amide

3-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (18 mg, 0.03 mmol)was dissolved in methanol (1 ml) and concentrated hydrochloric acid (1drop) added. The mixture was allowed to stir for 2 hours then evaporatedto dryness to give a residue. The residue was partitioned betweenaqueous saturated NaHCO₃ solution (10 ml), water (20 ml) and DCM (20ml). The organic layer was separated, dried over sodium sulphate,filtered and evaporated to give a yellow solid. The solid was purifiedby flash chromatography (Si-SPE, DCM:MeOH, gradient 98:2 to 92:8) toafford the title compound as a yellow solid (8 mg, 50%). LCMS (methodA): R_(T)=6.32 min, M+H⁺=504. ¹H NMR (d₄-MeOH, 400 MHz) 8.56 (s, 1H),8.34 (d, J=5.7 Hz, 1H), 7.87 (d, J=5.7 Hz, 1H), 7.45 (dd, J=10.5 Hz, 1.8Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.61 (dd, J=8.5 Hz, 8.5 Hz, 1H),3.89-3.94 (m, 1H), 3.76-3.85 (m, 2H), 3.45-3.54 (m, 2H).

Example 63-(4-Bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

A mixture of3-(4-bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acidethyl ester (36 mg, 0.09 mmol), 1N aqueous NaOH solution (0.10 ml, 0.10mmol) and methanol (2 ml) was heated at 65° C. for 45 minutes. Thereaction mixture was concentrated in vacuo then azeotroped with toluene(2×2 ml) to give a solid residue. The solid residue was dissolved inanhydrous THF (2 ml) andO—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (22 mg, 0.18mmol), EDCI (22 mg, 0.12 mmol), HOBt (17 mg, 0.13 mmol) and DIPEA (48μl, 0.28 mmol) were added. After stirring overnight at ambienttemperature, the reaction mixture was concentrated in vacuo to afford ayellow residue. The resultant residue was dissolved in ethyl acetate (30ml), washed with water (20 ml) followed by brine (10 ml) before theorganic layer was isolated then dried over sodium sulfate andconcentrated in vacuo to afford a yellow oil. The oil was purified byflash chromatography (Si-SPE, pentane:ethyl acetate, gradient 90:10 to50:50) to afford the title compound as a yellow oil (18 mg, 41%). LCMS(method B): R_(T)=3.03 min, M+H⁺=496/498.

3-(4-Bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid((R)-2,3-dihydroxy-propoxy)-amide

A solution of3-(4-bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (18 mg, 0.036 mmol)in methanol (1 ml) was loaded onto an Isolute® SCX-2 cartridge (5 g).The cartridge was then washed with methanol (15 ml) before the desiredproduct was eluted using 2M ammonia in MeOH and the eluent collectedthen concentrated to give a residue. The residue was purified by flashchromatography (Si-SPE, DCM:MeOH, gradient 100:0 to 94:6) to afford thetitle compound as an off white solid (9 mg, 53%): LCMS (method A):R_(T)=5.59 min, M+H⁺=456/458. ¹H NMR (d₄-MeOH, 400 MHz) 8.60 (s, 1H),8.40 (d, J=5.7 Hz, 1H), 7.94 (d, J=5.7 Hz, 1H), 7.39 (dd, J=10.6 Hz, 2.2Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.80 (dd, J=8.5 Hz, 8.5 Hz, 1H),4.01-4.10 (m, 1H), 3.89-4.00 (m, 2H), 3.57-3.67 (m, 2H).

Example 7 3-Chloro-isonicotinic acid ethyl ester

A suspension of 3-chloro-isonicotinic acid (1.0 g, 6.35 mmol) in thionylchloride (10 ml) was heated under reflux for 2.5 hours. After cooling toambient temperature, the solution was concentrated to dryness and thenazeotroped with toluene (10 ml) to afford an oil. The resultant oil wasadded dropwise over 10 minutes to a cooled (0° C.) solution of ethanol(15 ml) and DIPEA (5 ml). The reaction was stirred at room temperaturefor 18 hours then concentrated in vacuo before water (20 ml) was added.The solution was extracted with ethyl acetate (30 ml) and the organicphase was dried over sodium sulfate then concentrated to give the titlecompound as an orange oil (1.1 g, 94%). 1H NMR (CDCl₃, 400 MHz) 8.72 (s,1H), 8.59 (d, J=4.9 Hz, 1H), 7.63 (dd, J=4.9 Hz, 0.5 Hz, 1H), 4.44 (q,J=7.3 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H).

3-Hydroxy-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester

To a cooled (5° C.) stirred solution of 3-chloro-isonicotinic acid ethylester (1.11 g, 6.0 mmol) and mercapto-acetic acid ethyl ester (1.8 ml,16.7 mmol) in anhydrous DMF (20 ml), under an argon atmosphere, wasadded sodium hydride (15.6 mmol, 60% dispersion in oil, 622 mg) inportions over 20 minutes. Stirring was continued at 5° C. for 20minutes, followed by 18 hours at room temperature. The reaction mixturewas then quenched by the addition of water (5 ml), acidified by theaddition of acetic acid (1 ml), and subsequently concentrated to providea residue. The residue was partitioned between ethyl acetate (150 ml)and water (50 ml). The organic phase was isolated, dried over sodiumsulphate, filtered and evaporated to give a yellow oil. The oil waspurified by flash chromatography (Si-SPE, pentane:ethyl acetate,gradient 80:20 to 30:70) to afford the title compound as a yellow solid(1.33 g, 99%). LCMS (method B): R_(T)=2.57 min, M+H⁺=224.

3-(Nonafluorobutane-1-sulfonyloxy)-thieno[2,3-c]pyridine-2-carboxylicacid ethyl ester

To a stirred solution of 3-hydroxy-thieno[2,3-c]pyridine-2-carboxylicacid ethyl ester-(950 mg, 4.26 mmol) and DMAP (26 mg, 0.21 mmol) in DCM(12 ml) at 0° C. was added DIPEA (1.8 ml, 10.2 mmol) andnonafluorobutylsulfonyl fluoride (0.99 ml, 5.53 mmol). After 10 minutesthe reaction mixture was warmed to room temperature and stirred for anadditional 20 hours. The reaction mixture was diluted with DCM (30 ml)and washed with water (20 ml). The organic phase was dried over sodiumsulphate, filtered and evaporated to give a yellow oil. The oil waspurified by flash chromatography (Si-SPE, pentane:diethyl ether,gradient 90:10 to 65:35) to afford the title compound as a colourlessoil which crystallised on standing (678 mg, 31%): LCMS (method B).R_(T)=4.49 min, M+H⁺=508.

3-(4-Bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acidethyl ester

A degassed solution of3-(nonafluorobutane-1-sulfonyloxy)-thieno[2,3-c]pyridine-2-carboxylicacid ethyl ester (678 mg, 1.33 mmol), 4bromo -2-fluoroaniline (329 mg,1.73 mmol), Pd₂ dba₃ (61 mg, 0.07 mmol), Xantphos (78 mg, 0.14 mmol) andDBU (509 μl, 3.35 mmol) in toluene (3 ml) was subjected to mnicrowaveirradiation at 150° C. for 10 minutes. The reaction mixture was cooledto ambient temperature then diluted with ethyl acetate (70 ml). Theresultant solution was washed with water (20 ml), dried over sodiumsulfate and concentrated in vacuo to give an orange oil. The oil waspurified by flash chromatography (Si-SPE, pentane:diethyl ether,gradient 90:10 to 50:50) followed by crystallisation from ethylacetate:pentane to provide the title compound as a white solid (353 mg,67%). LCMS (method B): R_(T)=4.08 min, M+H⁺=395/397.

3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acidethyl ester

A mixture of3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acidethyl ester (288 mg, 0.73 mmol), copper (1) iodide (7 mg, 0.036 mmol),sodium iodide (219 mg, 1.46 mmol) andtrans-N,N′-dimethyl-1,2-cyclohexane diamine (10.4 mg, 0.073 mmol) in1,4-dioxane (1.0 ml) was heated at 105° C. for 24 hours under an argonatmosphere. Copper (I) iodide (7 mg, 0.036 mmol) andtrans-N,N′-dimethyl-1,2-cyclohexane diamine (10.4 mg, 0.073 mmol) wereadded and heating continued for a further 24 hours. The reaction wascooled to room temperature and the mixture was partitioned between DCM(30 ml), concentrated aqueous ammonia (2 ml) and water (13 ml). Theorganic layer was isolated, dried over sodium sulphate, filtered andevaporated then the residue was purified by flash chromatography(Si-SPE, DCM) to afford the title compound as a yellow solid (275 mg,85%). LCMS (method B): R_(T)=4.23 min, M+H⁺=443.

3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

A mixture of3-(2-fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acidethyl ester (50 mg, 0.11 mmol), 1N aqueous NaOH solution (0.12 ml, 0.12mmol) and ethanol (2 ml) was heated at 65° C. for 45 minutes. Thereaction mixture was concentrated then azeotroped with toluene (2×2 ml)to give a solid residue. The solid residue was dissolved in anhydrousTHF (4 ml) andO—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (27 mg, 0.23mmol), EDCI (27 mg, 0.14 mmol), HOBt (21 mg, 0.16 mmol) and DIPEA (59μl, 0.34 mmol) were added. After stirring for 19 hours the solvent wasevaporated and the residue partitioned between ethyl acetate (20 ml) andwater (15 ml). The organic layer was isolated, dried over sodiumsulphate, filtered and evaporated to give a brown oil. The oil waspurified by flash chromatography (Si-SPE, pentane:ethyl acetate,gradient 80:20 to 0:100) to afford the title compound as an orange oil(40 mg, 66%). LCMS (method B): R_(T)=3.30 min, M+H⁺=544.

3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid((R)-2,3-dihydroxy-propoxy)-amide

3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (40 mg, 0.07 mmol)was dissolved in methanol (1 ml) and concentrated hydrochloric acid (1drop) added. The mixture was allowed to stir for 2 hours then evaporatedto dryness to give a residue. The residue was partitioned betweenaqueous saturated NaHCO₃ solution (3 ml), water (20 ml) and DCM (20 ml).The organic layer was separated, dried over sodium sulphate, filteredand evaporated to give a yellow solid. The solid was purified by flashchromatography (Si-SPE, DCM:MeOH, gradient 99:1 to 92:8) to afford thetitle compound as a yellow solid (21 mg, 57%). LCMS (method A):R_(T)=7.12 min, M+H⁺=504. ¹H NMR (d₄-MeOH, 400 MHz) 9.15 (s, 1H), 8.38(d, J=5.7 Hz, 1H), 7.52 (dd, J=10.6 Hz, 2.0 Hz, 1H), 7.44 (dd, J=5.7 Hz,1.0 Hz, 1H), 7.32 (ddd, J=8.5 Hz, 2.0 Hz, 1.0 Hz, 1H), 6.56 (dd, J=8.5Hz, 8.5 Hz, 1H), 4.00-4.13 (m, 1H), 3.85-3.95 (m, 2H), 3.54-3.65 (m,2H).

Example 83-(4-Bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide

A mixture of ethyl3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylate (63mg, 0.16 mmol), 1N aqueous NaOH solution (0.17 ml, 0.17 mmol) andethanol (2 ml) was heated at 65° C. for 45 minutes. The resultantreaction mixture was concentrated in vacuo then the residue wasazeotroped with toluene (2×2 ml) to give a solid residue. The resultantsolid residue was suspended in anhydrous THF (2 ml) beforeO—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (38 mg, 0.32mmol), EDCI (38 mg, 0.20 mmol), HOBt (30 mg, 0.22 mmol) and DIPEA (83μl. 0.48 mmol) were added. After stirring for 66 hours at ambienttemperature, the reaction mixture was concentrated in vacuo to afford ayellow residue. The resultant residue was dissolved in ethyl acetate (50ml) and washed with water (20 ml), before the organic layer wasisolated, dried over sodium sulfate, then concentrated in vacuo toafford a yellow oil. The oil was purified by flash chromatography(Si-SPE, pentane:ethyl acetate, gradient 60:40 to 0:100) to afford thetitle compound as a yellow foam (61 mg, 77%). LCMS (method B):R_(T)=3.02 min, M+H⁺=496/498.

3-(4-Bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid((R)-2,3-dihydroxy-propoxy)-amide

A solution 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide(61 mg, 0.12 mmol) and 1 drop of concentrated HCl in methanol (2 ml) wasstirred at ambient temperature for 2 hours. The solvent was evaporatedin vacuo and the resultant residue partitioned between dichloromethane(20 ml), water (10 ml) and saturated NaHCO₃ solution (3 ml). The organicphase was dried over sodium sulfate and concentrated in vacuo to afforda yellow oil. The resultant yellow oil was purified by flashchromatography (Si-SPE, DCM:MeOH, gradient 99:1 to 92:8) followed bytrituration with methanol/acetonitrile to afford the title compound asan off-yellow solid (15 mg, 26%): LCMS (method A): R_(T)=6.01 min,M+H⁺=456/458. ¹H NMR (d₄-MeOH, 400 MHz) 9.16 (d, J=0.8 Hz, 1H), 8.38 (d,J=5.8 Hz, 1H), 7.37-7.46 (m, 2H), 7.17 (ddd, J=8.6 Hz, 2.3 Hz, 2.2 Hz,1H), 6.72 (dd, J=8.7 Hz, 8.7 Hz, 1H), 4.00-4.05 (m, 1H), 3.84-3.96 (m,2H), 3.53-3.64 (m, 2H).

Example 93-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid(2-vinyloxy-ethoxy)-amide

A mixture of3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acidethyl ester (124 mg, 0.28 mmol), 1N aqueous NaOH solution (0.30 ml, 0.30mmol) and ethanol (4 ml) was heated at 65° C. for 45 minutes. Thereaction mixture was concentrated in vacuo then the resultant residuewas azeotroped with toluene (2×2 ml) to give a solid residue. The solidresidue was dissolved in anhydrous THF (4 ml) beforeO-(2-vinyloxy-ethyl)-hydroxylamine (58 mg, 0.56 mmol), EDCI (67 mg, 0.35mmol), HOBt (53 mg, 0.39 mmol) and DIPEA (147 μl, 0.84 mmol) were added.After stirring for 18 hours at ambient temperature the solvent wasevaporated and the resultant residue was diluted with water (20 ml),then extracted with ethyl acetate (30 ml) followed by dichloromethane(30 ml). The combined organic layers were dried over sodium sulfate,filtered and evaporated to give a yellow oil. The resultant yellow oilwas purified by flash chromatography (Si-SPE, dichloromethane:methanol,gradient 100:0 to 98:2) to afford the title compound as a yellow solid(91 mg, 65%). LCMS (method B): R_(T)=3.05 min, M+H⁺=500.

Example 103-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid(2-hydroxyethoxy)-amide

3-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid(2-vinyloxy-ethoxy)-amide (91 mg, 0.18 mmol) was dissolved in ethanol (2ml) and 1M hydrochloric acid (0.5 ml) added. The mixture was allowed tostir for 2 hours then evaporated to dryness to give a residue. Theresultant residue was partitioned between aqueous saturated NaHCO₃solution (3 ml), water (20 ml) and DCM (20 ml). The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated to give ayellow solid. The resultant yellow solid was purified by flashchromatography (Si-SPE, DCM:MeOH, gradient 100:0 to 98:2) followed byreversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl, 0.1% TFA in wateron a gradient of methanol 95:5 to 40:60) to afford the title compound asa yellow solid (34 mg, 40%). LCMS (method A): R_(T)=6.00 min, M+H⁺=474.¹H NMR (d₄-MeOH, 400 MHz) 8.68 (s, 1H), 8.44 (d, J=5.7 Hz, 1H), 7.98(dd, J=5.7 Hz, 0.8 Hz, 1H), 7.55 (dd, J=10.5 Hz, 1.8 Hz, 1H), 7.35-7.40(m, 1H), 6.7 (dd, J=8.5 Hz, 8.5 Hz, 1H), 3.98 (t, J=Hz, 2H), 3.74 (t,J=Hz, 2H).

Example 11

3-Amino-7-fluoro-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester

To a mixture of 4-chloro-5-fluoro-nicotinonitrile (1.0 g, 6.4 mmol) andpotassium carbonate (4.4 g, 32 mmol) in DMF (15 mL) at 0° C. was addedethyl thioglycolate (0.73 mL, 6.7 mmol) dropwise. The reaction mixturewas stirred at 0° C. for 10 min, at room temperature for 20 min and thenat 40° C. for 30 min. The reaction mixture was cooled to roomtemperature and partitioned between water and ethyl acetate. The organiclayer was separated and washed with water followed by brine, dried oversodium sulphate and concentrated in vacuo to give the title compound asa yellow solid (1.5 g, quant.). LCMS (method B): R_(T)=3.41 min,M+H⁺=241.

7-Fluoro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester

A mixture of 3-amino-7-fluoro-thieno[3,2-c]pyridine-2-carboxylic acidethyl ester (360 mg, 1.5 mmol), trifluoro-methanesulfonic acid2-fluoro-4-trimethylsilanyl-phenyl ester (411 mg, 1.3 mmol), Pd₂ dba₃(69 mg, 0.075 mmol), Xantphos (86 mg, 0.15 mmol) and Cs₂CO₃ (685 mg, 2.1mmol) in toluene (6 ml) was subjected to microwave irradiation at 160°C. for 20 minutes. The reaction mixture was filtered through a pad ofCelite®. The filtrate was concentrated under reduced pressure to give aresidue which was subjected to flash chromatography (Si-SPE,pentane:diethyl ether, gradient 100:0 to 90:10) to give the titlecompound as a yellow solid (338 mg, 55%). LCMS (method B): R_(T)=5.20min, M+H⁺=407.

7-Fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester

To a cooled (0° C.) solution of7-fluoro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester (330 mg, 0.81 mmol) in DCM (10 mL) was added iodinemonochloride (1M in DCM, 1.6 mL, 1.6 mmol) dropwise. On completeaddition the mixture was allowed to stir at 0° C. for 1 hour thenquenched by the addition of saturated sodium thiosulphate solution (10mL). The mixture was stirred vigorously for 10 min and partitionedbetween ethyl acetate and water. The organic layer was separated andwashed with a saturated solution of sodium hydrogenocarbonate followedby brine, dried over sodium sulphate, filtered and concentrated to givethe title compound as a yellow solid (358 mg, 54%). LCMS (method B):R_(T)=4.72 min, M+H⁺=461.

7-Fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid (2-vinyloxy-ethoxy)-amide

To a solution7-fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester (175 mg, 0.38 mmol) in IMS (4 mL) was added a 1.0 Maqueous solution of sodium hydroxide (0.5 mL, 0.5 mmol). The reactionmixture was heated to 65° C. for 1 hour before being cooled to roomtemperature and concentrated in vacuo. The resulting residue wasazeotroped with toluene (3×10 mL), and then suspended in THF (5 mL).O-(2-Vinyloxy-ethyl)-hydroxylamine (78 mg, 0.76 mmol),N—N-diisopropylethylamine (0.26 mL, 1.52 mmol), EDCI (146 mg, 0.76mmol), and HOBt (103 mg, 0.76 mmol) were then added sequentially, andthe reaction mixture stirred for 18 hours at room temperature. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between water and ethyl acetate. The organic layer wasseparated and washed with a saturated solution of sodiumhydrogenocarbonate and brine, dried over sodium sulfate, filtered andconcentrated to give a residue, which was purified by columnchromatography (Si-SPE, gradient 0-2% methanol in DCM) to afford thetitle compound as a pale yellow solid (106 mg, 54%). LCMS (method B):R_(T)=3.92 min. M+H⁺=518.

7-Fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid (2-hydroxy-ethoxy)-amide

A solution of7-fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid (2-vinyloxy-ethoxy)-amide (100 mg, 0.19 mmol) in a mixture ofmethanol and DCM was loaded onto a 5 g SCX-2 cartridge, which was elutedwith methanol followed by a 2M solution of ammonia in methanol.Appropriate fractions were combined and concentrated under reducedpressure. The residual solid was purified by column chromatography(Si-SPE, gradient 0-40% tert-butyl dimethyl ether in DCM then 10%methanol in DCM) to afford the title compound as a yellow solid (50 mg,53%). LCMS (method A): R_(T)=9.60 min, M+H⁺=492. 1H NMR (CD₃OD, 400 MHz)3.58 (2H, t, J=4.89 Hz), 3.84 (2H, t, J=4.91 Hz), 6.89 (1H, t, J=8.76Hz), 6.98 (1H, dd, J=8.41, 2.15 Hz), 7.21-7.26 (1H, m), 8.02 (1H, d,J=5.61 Hz), 8.45 (1H, dd, J=8.25, 5.61 Hz), 8.53-8.59 (1H, m).

Example 12

3-(2-Fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester

A degassed solution of3-(nonafluorobutane-1-sulfonyloxy)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester (0.74 g, 1.5 mmol), 2fluoro-4-methylsulfanyl-phenylamine (0.12 g, 0.76 mmol), Pd₂ dba₃ (0.035 g,0.038 mmol), Xantphos (0.044 g, 0.076 mmol) and K₃PO₄ (0.32 g, 1.5 mmol)in toluene (10 ml) was heated at reflux for 18 hours. The reactionmixture was cooled to ambient temperature then filtered through a pad ofHyflo washing with ethyl acetate. The filtrate was concentrated in vacuoand the resultant residue subjected to flash chromatography (Si-SPE,gradient 0-10% ethyl acetate in dichloromethane) to provide the titlecompound as a yellow solid (0.16 g, 57%). LCMS (method B): R_(T)=3.84min, M+H⁺ 363.

3-(2-Fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid

A suspension of3-(2-fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid ethyl ester (0.19 g, 0.52 mmol) in IMS (10 ml) was treated withsodium hydroxide (1M aqueous solution, 0.63 ml) and the reaction mixtureheated at 60° C. for 3 hours. The resultant mixture was allowed to coolthen concentrated in vacuo. The crude residue was treated with water andthe mixture adjusted to pH 5 with acetic acid. The resultant suspensionwas filtered, the residue collected and dried in vacuo to give the titlecompound as a green solid (0.107 g, 56%) which was used withoutpurification in the subsequent step.

3-(2-Fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide

A suspension of3-(2-fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid (0.107 g, 0.32 mmol) in dry dichloromethane (5 ml) under anatmosphere of nitrogen was cooled to 0° C. and treated with DMF (1 drop)and oxalyl chloride (0.081 ml, 0.96 mmol). The reaction mixture wasstirred for 1 hour then the solvent removed in vacuo. The resultantresidue was re-suspended in dry dichloromethane (1 ml) and treateddropwise with a solution of O-(2-vinyloxy-ethyl) -hydroxylamine (0.066g, 0.64 mmol) and DIPEA (0.167 ml, 0.96 mmol) in dry dichloromethane (4ml) before being stirred for 18 hours. The reaction mixture was washed(water, brine), dried (MgSO₄), filtered and concentrated in vacuo. Theresultant residue was subjected to flash chromatography (Si-SPE,gradient 0-30% ethyl acetate in dichloromethane) to provide the titlecompound as a yellow solid (0.024 g, 18%). LCMS (method B): R_(T)=3.17min, M+H⁺ 420.

3-(2-Fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-ethoxy)-amide

3-(2-Fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylicacid (2-vinyloxy-ethoxy)-amide (20 mg, 0.048 mmol) was dissolved inmethanol (1 ml) and treated with concentrated hydrochloric acid (0.01ml, 0.12 mmol) before being stirred at room temperature for 2 hours. Thereaction mixture was concentrated in vacuo and the resultant residuesubjected to reverse phase HPLC (0.1% HCO₂H in water on a gradient ofacetonitrile). The appropriate fractions were combined and freeze-driedto give the title compound (9 mg, 47%). LCMS (method A): R_(T)=6.36 min,M+H⁺ 394; 1H NMR (DMSO-d₆, 400 MHz) 3.58 (2H, t, J=4.89 Hz), 3.84 (2H,t, J=4.91 Hz), 6.89 (1H, t, J=8.76 Hz), 6.98 (1H, dd, J=8.41, 2.15 Hz),7.21-7.26 (1H, m), 8.02 (1H, d, J=5.61 Hz), 8.45 (1H, dd, J=8.25, 5.61Hz), 8.53-8.59 (1H, m).

1. A compound selected from Formula I:

and salts thereof, wherein: Z¹ is CR¹; Z² is N; Z³ is CR³; Z⁴ is CR⁴;R¹, R³ and R⁴ are independently selected from H, halo, CN, CF₃, —OCF₃,—NO₂, —(CR¹⁴R¹⁵)_(n)C(═Y)R¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y)OR¹¹,—(CR¹⁴R¹⁵)_(n)C(═Y)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)SR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹²C(═Y)OR¹¹, —(CR¹⁴R¹⁵)_(n)NR¹³C(═Y)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y)R¹¹,—(CR¹⁴R¹⁵)_(n)OC(═Y)OR¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)OS(O)₂(OR¹¹), —(CR¹⁴R¹⁵)_(n)OP(═Y)(OR¹¹)(OR¹²),—(CR¹⁴R¹⁵)_(n)OP(OR¹¹)(OR¹²), —(CR¹⁴R¹⁵)_(n)S(O)R¹¹,—(CR¹⁴R¹⁵)_(n)S(O)₂R¹¹, —(CR¹⁴R¹⁵)_(n) S(O)₂NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)S(O)(OR¹¹), —(CR¹⁴R¹⁵)_(n)S(O)₂(OR¹¹),—(CR¹⁴R¹⁵)_(n)SC(═Y)R¹¹, —(CR¹⁴R¹⁵)_(n)SC(═Y)OR¹¹,—(CR¹⁴R¹⁵)_(n)SC(═Y)NR¹¹R¹², C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl; W is

R⁵ and R⁶ are independently selected from H or C₁-C₁₂ alkyl; X¹ isselected from R¹¹, —OR¹¹, —NR¹¹R¹², —S(O)₂R¹¹, and —S(O)₂R¹¹; when X¹ isR¹¹ or —OR¹¹, R¹¹ or —OR¹¹ of X¹ and —R⁵ are optionally taken togetherwith the nitrogen atom to which oxo, —Si(C₁-C₆ alkyl),—(CR¹⁹R²⁰)_(n)C(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)Or¹⁶,—(CR¹⁹R²⁰)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁶R¹⁷, —(CR¹⁹R²⁰)_(n)OR¹⁶,—(CR¹⁹R²⁰)_(n)SR¹⁶, —(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁹R²⁰)_(n)NR¹⁸C(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)R¹⁶,—(CR¹⁹R²⁰)_(n)OC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)OS(O)₂(OR¹⁶), —(CR¹⁹R²⁰)_(n)OP(═Y′)(OR¹⁶)(OR¹⁷),—(CR¹⁹R²⁰)_(n)OP(OR¹⁶)(OR¹⁷), —(CR¹⁹R²⁰)_(n)S(O)R¹⁶,—(CR¹⁹R²⁰)_(n)S(O)₂R¹⁶, —(CR¹⁹R²⁰)_(n)S(O)₂NR¹⁶R¹⁷,—(CR¹⁹R²⁰)_(n)S(O)(OR¹⁶), —(CR¹⁹R²⁰)_(n) S(O)₂(OR¹⁶),—(CR¹⁹R²⁰)_(n)SC(═Y′)R¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)OR¹⁶, —(CR¹⁹R²⁰)_(n)SC(═Y′)NR¹⁶R¹⁷, and R²¹; each R¹⁶, R¹⁷ and R¹⁸ is independently H,C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl,carbocyclyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore groups selected from halo, CN, —OCF₃, CF₃, —NO₂, C₁-C₆ alkyl, —OH,—SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl),and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl); or R¹⁶ and R¹⁷ together with thenitrogen to which they are attached form a 3-8 membered saturated,unsaturated or aromatic ring having 0-2 heteroatoms selected from O, Sand N, wherein said ring is optionally substituted with one or moregroups selected from halo, CN, —OCF₃, CF₃, —NO₂, C₁-C₆ alkyl, —OH, —SH,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆ alkyl)₂,—OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyOC(O)N(C₁-C₆ alkyl)₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl),and —N(C₁-C₆ alky)C(O)O(C₁-C₆ alkyl); R¹⁹ and R²⁰ are independentlyselected from H, C₁-C₁₂ alkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-carbocyclyl,—(CH₂)_(n)-heterocyclyl, and —(CH₂)_(n)-heteroaryl; R²¹ is C₁-C₁₂ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein each member of R²¹ is optionally substituted withone or more groups selected from halo, oxo, CN, —OCF₃, CF₃, —NO₂, C₁-C₆alkyl, —OH, —SH,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl),—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl),—SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆alkyl)₂, —OC(O)O(C₁-C₆ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl); each Y′ is independentlyO, NR²², or S; and R²² is H or C₁-C₁₂ alkyl.
 2. The compound of claim 1wherein X^(1 is selected from:)


3. The compound of claim 1 wherein X¹ is selected from:


4. The compound of claim 1 wherein X¹ is R¹¹, and R¹¹ and R⁵ are takentogether with the nitrogen atom to which they are attached to form:


5. The compound of claim 1 wherein X² is:


6. The compound of claim 1 wherein R^(1l) is selected from H, CH₃, CF₃,CN, —NR¹¹R¹², —OR¹¹, and Cl.
 7. The compound of claim 1 wherein R³ isselected from H, CH₃, F, or CF₃.
 8. The compound of claim 1 wherein R⁴is selected from CF₃, Br, Cl, CN, —NR¹¹R¹², —OR¹¹, and —C(═O)NR¹¹R¹². 9.The compound of claim 8 wherein R⁴ is selected from Cl, Br, Me, Et, F,CHF₂, CF₃ or —OH.
 10. The compound of claim 1 wherein R⁵ is H or methyl.11. The compound of claim 1 wherein R⁶ is H or methyl.
 12. A compoundselected from:


13. A pharmaceutical composition comprising a compound of any one ofclaims 1, 2-11, and 12, and a pharmaceutically acceptable carrier. 14.The pharmaceutical composition of claim 13, further comprising a secondchemotherapeutic agent.